Active transdermal technologies such as microneedle devices can expand the drugs that can be delivered transdermally to include small molecule drugs (e.g., drugs having a molecular weight greater than 500 Da) and biomolecules (e.g., peptides, proteins, and nucleic acids) by creating breaches in the stratum corneum that provide pathways for drug transport. However, the skin's healing mechanisms limit the duration of this effect, since the skin gradually recovers to an intact condition. Thus, the enhanced drug delivery made possible by active transdermal technologies such as microneedle devices is limited by the skin's healing processes, and gradually ceases as the skin heals. As a result, active transdermal technologies generally are not useful to achieve drug delivery over a sustained period of time.
Speaking generally, the skin healing mechanism is divided into three processes: inflammation, proliferation, and skin remodeling. See G. Broughton et al., “The Basic Science of Wound Healing,” Plastic and Reconstructive Surgery 117(7 Suppl.): 12S-34S (June 2006); P. Ghosh et al., “Effect of formulation pH on transport of naltrexone species and pore closure in microneedle-enhanced transdermal drug delivery,” Molecular Pharm. 10:2331-2339 (Jun. 3, 2013). Inhibiting these processes and extending the lifetime of open microchannels created by active transdermal technologies may prolong the time period during which enhanced drug delivery can be achieved. In this regard, some anti-inflammatory drugs, such as diclofenac, have been reported to extend the lifetime of microchannels. See N. K. Brogden et al., “Diclofenac delays micropore closure following microneedle treatment in human subjects,” J. Control Release 163:220-229 (Aug. 21, 2012); N. K. Brogden et al., “Diclofenac Enables Unprecedented Week-Long Microneedle-Enhanced Delivery of a Skin Impermeable Medication in Humans,” Pharm. Res. 30:1947-1955 (Aug. 1, 2013); P. Ghosh et al., “Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin,” Pharm. Res. 31:148-159 (January 2014). Also, HMG-CoA reductase inhibitors, such as fluvastatin, have been reported to extend the lifetime of microchannels. See P. Ghosh et al., “Fluvastatin as a Micropore Lifetime Enhancer for Sustained Delivery Across Microneedle-Treated Skin,” J. Pharm. Sci. 103:652-660 (Jan. 6, 2014). However, the use of agents that themselves are active pharmaceutical ingredients (APIs) presents drawbacks due to their pharmaceutical activity and accompanying side effects, which limits their use to specific patient populations, and which may prevent their use in combination with other drugs.
Thus, there remains a need for compositions and methods for achieving sustained drug delivery using active transdermal technologies.